Developing Metal-Binding Isosteres of 8-Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds

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Abstract
The use of metal-binding pharmacophores (MBPs) in fragment-based drug discovery (FBDD) has proven effective for targeted metalloenzyme drug development. However, MBPs can still suffer from pharmacokinetic liabilities, such as poor solubility and low membrane permeability. Bioisostere replacement is an effective strategy utilized by medicinal chemists to navigate these issues during the drug development process. The quinoline pharmacophore and its bioisosteres, such as quinazoline, are important building blocks to modulate drug-target interactions and physicochemical properties in the design of new therapeutics. More relevant to metalloenzyme inhibition, 8-hydroxyquinoline (8-HQ) and its derivatives can serve as MBPs for metalloenzyme inhibition. In this report, 8-HQ isosteres are designed and the coordination chemistry of the resulting metal-binding isosteres (MBIs) is explored using a bioinorganic model complex. In addition, the physicochemical properties and metalloenzyme inhibition activity of these MBIs were investigated to establish drug-like profiles. This report provides a new group of 8-HQ-derived MBIs that can serve as novel scaffolds for metalloenzyme inhibitor development with tunable, and potentially improved, physicochemical properties.
Funding Information
  • Schweizerischer Nationalfonds zur F?rderung der Wissenschaftlichen Forschung (P2EZP2_195505)
  • National Institute of Allergy and Infectious Diseases (R01 AI149444)

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